Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis

Claire T Deakin; John Bowes; Lisa G Rider; Frederick W Miller; Lauren M Pachman; Helga Sanner; Kelly Rouster-Stevens; Gulnara Mamyrova; Rodolfo Curiel; Brian M Feldman; Adam M Huber; Ann M Reed; Heinrike Schmeling; Charlotte G Cook; Lucy R Marshall; Meredyth G Ll Wilkinson; Stephen Eyre; Soumya Raychaudhuri; Lucy R Wedderburn; Juvenile Dermatomyositis Cohort and Biomarker Study, the Childhood Myositis Heterogeneity Study Group, and the Myositis Genetics Consortium (MYOGEN)

doi:10.1093/hmg/ddac019

Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis

Hum Mol Genet. 2022 Jul 21;31(14):2471-2481. doi: 10.1093/hmg/ddac019.

Authors

Claire T Deakin^{1

2

3}, John Bowes^{4

5}, Lisa G Rider⁶, Frederick W Miller⁶, Lauren M Pachman⁷, Helga Sanner^{8

9}, Kelly Rouster-Stevens¹⁰, Gulnara Mamyrova¹¹, Rodolfo Curiel¹¹, Brian M Feldman¹², Adam M Huber¹³, Ann M Reed¹⁴, Heinrike Schmeling¹⁵, Charlotte G Cook¹, Lucy R Marshall^{1

2

3}, Meredyth G Ll Wilkinson^{1

2

3}, Stephen Eyre^{4

5}, Soumya Raychaudhuri^{4

5

16

17}, Lucy R Wedderburn^{1

2

3}; Juvenile Dermatomyositis Cohort and Biomarker Study, the Childhood Myositis Heterogeneity Study Group, and the Myositis Genetics Consortium (MYOGEN)

Affiliations

¹ Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
² Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCL Hospital and Great Ormond Street Hospital, London, UK.
³ NIHR Biomedical Research Centre at Great Ormond Street Hospital, London, UK.
⁴ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
⁵ National Institute of Health Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
⁶ Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
⁷ Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁸ Department of Rheumatology, University of Oslo, Oslo, Norway.
⁹ Oslo New University College, Oslo, Norway.
¹⁰ Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Division of Rheumatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
¹² Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
¹³ IWK Health Centre and Dalhousie University, Halifax, NS, Canada.
¹⁴ Pediatrics, Duke University, Durham, NC, USA.
¹⁵ Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
¹⁶ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁷ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Abstract

Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy of children. JDM and adult-onset dermatomyositis (DM) have similar clinical, biological and serological features, although these features differ in prevalence between childhood-onset and adult-onset disease, suggesting that age of disease onset may influence pathogenesis. Therefore, a JDM-focused genetic analysis was performed using the largest collection of JDM samples to date. Caucasian JDM samples (n = 952) obtained via international collaboration were genotyped using the Illumina HumanCoreExome chip. Additional non-assayed human leukocyte antigen (HLA) loci and genome-wide single-nucleotide polymorphisms (SNPs) were imputed. HLA-DRB1*03:01 was confirmed as the classical HLA allele most strongly associated with JDM [odds ratio (OR) 1.66; 95% confidence interval (CI) 1.46, 1.89; P = 1.4 × 10-14], with an independent association at HLA-C*02:02 (OR = 1.74; 95% CI 1.42, 2.13, P = 7.13 × 10-8). Analyses of amino acid positions within HLA-DRB1 indicated that the strongest association was at position 37 (omnibus P = 3.3 × 10-19), with suggestive evidence this association was independent of position 74 (omnibus P = 5.1 × 10-5), the position most strongly associated with adult-onset DM. Conditional analyses also suggested that the association at position 37 of HLA-DRB1 was independent of some alleles of the Caucasian HLA 8.1 ancestral haplotype (AH8.1) such as HLA-DQB1*02:01 (OR = 1.62; 95% CI 1.36, 1.93; P = 8.70 × 10-8), but not HLA-DRB1*03:01 (OR = 1.49; 95% CR 1.24, 1.80; P = 2.24 × 10-5). No associations outside the HLA region were identified. Our findings confirm previous associations with AH8.1 and HLA-DRB1*03:01, HLA-C*02:02 and identify a novel association with amino acid position 37 within HLA-DRB1, which may distinguish JDM from adult DM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Amino Acids / genetics
Child
Dermatomyositis* / diagnosis
Dermatomyositis* / genetics
Genetic Predisposition to Disease
HLA-C Antigens / genetics
HLA-DRB1 Chains* / genetics
Haplotypes / genetics
Humans
Myositis* / diagnosis
Myositis* / genetics

Substances

Amino Acids
HLA-C Antigens
HLA-DRB1 Chains

Abstract

Publication types

MeSH terms

Substances

Grants and funding